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Suvorexant, a Clinically Used Dual Orexin Receptor Antagonist, Induces Human Pregnane X Receptor‐Mediated Expression of Cytochrome P450 3A4
Author(s) -
Abbott Kodye,
Pondugula Satyanarayana
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.lb549
Subject(s) - pregnane x receptor , cyp3a4 , transactivation , pharmacology , chemistry , medicine , nuclear receptor , gene expression , cytochrome p450 , gene , transcription factor , biochemistry , metabolism
Activation of human pregnane X receptor (hPXR)‐regulated expression of cytochrome p450 3A4 (CYP3A4) plays an important role in mediating adverse drug interactions. Here, we studied whether suvorexant, a dual orexin receptor antagonist used to treat insomnia, could induce hPXR‐mediated regulation of CYP3A4. hPXR transactivation assays were performed to determine CYP3A4 promoter activity and in HepG2 human liver carcinoma cells as well as in LS174T and LS180 human colon cancer cells. Quantitative RT‐PCR assays were conducted to study gene expression of CYP3A4 in human primary hepatocytes and hepatocells. Suvorexant, at its therapeutically‐relevant concentrations, induced hPXR transactivation of CYP3A4 promoter activity. Similar to a known PXR agonist rifampicin, suvorexant also induced CYP3A4 gene expression in human primary hepatocytes and hepatocells. These results suggest that suvorexant induces hPXR‐regulated CYP3A4 gene expression. As insomnia often coexists with other medical and psychiatric conditions, it is treated concurrently with the coexisting conditions. Therefore, the inductive effects of suvorexant on CYP3A4 expression caution the use of suvorexant in conjunction with other medications metabolized via CYP3A4. Future studies will be directed to investigate the mechanisms of suvorexant induction of hPXR‐mediated CYP3A4 expression. Support or Funding Information This work was supported by the Auburn University Research Initiative in Cancer Grant, Animal Health and Disease Research Grant, and Auburn University Startup Funds to Pondugula SR. We thank Drs. Tao, Coleman, and Schwartz for sharing their facilities.